Note: Descriptions are shown in the official language in which they were submitted.
81802149
PROCESS FOR THE PREPARATION OF 4-ALKOXY-3-HYDROXYPICOLINIC ACIDS
[0001] This application claims the benefit of priority of U.S.
Provisional Patent
Applications Serial Nos. 62/021,876 filed July 8,2014, 62/021,877 filed July
8, 2014,
and 62/021,881 filed July 8, 2014.
Field
[0002] The present disclosure concerns a process for the preparation of 4-
alkoxy-3-
hydroxypicolinic acids. More particularly, the present disclosure concerns a
process for the
preparation of 4-alkoxy-3-hydroxypicolinic acids from furfural.
Background
[0003] U.S. Patent No. 6,521,622 B1 and U.S. Application Serial Numbers
61/747,723 and 14/142,183 describe inter cilia certain heterocyclic aromatic
amide compounds
of general Formula and their use as fungicides.
OR1
0
[0004] These disclosures also describe the preparation of 4-alkoxy-3-
hydroxypicolinic acids as key intermediates in the preparation of these
heterocyclic aromatic
amide compounds. It would be useful to have an efficient and scalable process
route to 4-
alkoxy-3-hydroxypicolinic acids from inexpensive raw materials.
Summary
[0005] The present disclosure concerns processes for the preparation of 4-
alkoxy-3-
hydroxypicolinic acids of Formula H
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OR1
LOH
wherein 1=Z1 is a C1-C3 alkyl;
from the compound of Formula A
LOH
Br
Br'sNCN
A
[0006] One aspect of the present disclosure are the novel intermediates
produced in
the present processes, viz., compounds selected from the group consisting of:
a)
NH3 + Br-
\ 0/ CN
b)
Br
Br N CN
OR1
BrN'CN
wherein R1 is a C1-C3 alkyl;
d)
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OR1
BrNCO2H
wherein R1 is a Ci-C3 alkyl; and
e)
OH
wherein R1 is a Ci-C3 alkyl.
Detailed Description
[0007] The terms "isolate," "isolating," or "isolation" as used herein mean
to
partially or completely remove the desired product from the other components
of a finished
chemical process mixture using standard methods such as, but not limited to,
filtration,
extraction, distillation, crystallization, centrifugation, trituration, liquid-
liquid phase
separation or other methods known to those of ordinary skill in the art. The
isolated product
may have a purity that ranges from <50% to > 50%, and may be purified to a
higher purity
level using standard purification methods. The isolated product may also be
used in a
subsequent process step with or without purification.
[0008] In the processes described herein 4-alkoxy-3-hydroxypicolinic acids
are
prepared from furfural in a series of chemical steps involving cyano-
amination, ammonium
salt formation, bromination/rearrangement, bromo substitution by an alkoxide
group, nitrile
hydrolysis, and halogen reduction. Some of the individual steps may be
performed in
different sequences of order.
[0009] Cyano(furan-2-yl)methanaminium chloride salts of Formula la have
been
prepared and used as intermediates in the preparation of 3-
hydroxpicolinonitriles and 3-
hydroxy- picolinoamides of Formula lb as described in Acta Chem. Scand. 19
(1965) pg.
1147-1152,
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NH3 C1 R2
0
'eNCN
R3 R2 N R4
la 1b
wherein R2 is H or methyl, R3 is H or 2-propyl, and R4 is CN or C(0)NH2.
A. Preparation of Compound of Formula A
[0010] In the process described herein, chemical steps a, b and c are
performed as
depicted in Scheme Ito prepare dibromohydroxypicolinonitrile A.
Scheme I
Br
O
0
NH3+ X-
a, bc OH
\ 0)2)N
CN
Br
A
[0011] The cyano(furan-2-yl)methanaminium halide salt of Formula D is
prepared by
first reacting furfural (Formula B) with at least one equivalent each of an
ammonia source
and
0 NH2 NI-13+ X-
"NH3" / "-CN" 0. \c HX 0 \17)N
CN ____________________________________________________ \r"µCN
a
a cyanide source (Step a) in a reaction known in the art as the Strecker
synthesis of a-
aminonitriles which is described in Organic Syntheses, Coll. Vol. I, page 21
and Coll. Vol.
III, pages 84 and 88 to provide the amino(furan-2-yl)acetonitrile of Formula
C. Suitable
ammonia sources include: ammonium salts such as, but not limited to, ammonium
acetate,
ammonium bromide, ammonium chloride, ammonium formate, ammonium sulfate and
ammonium cyanide; ammonia dissolved in an organic solvent such as, for
example, ammonia
in methanol, ammonia in ethanol and ammonia in dioxane; ammonia in water
(i.e.,
ammonium hydroxide); and liquid, anhydrous ammonia or gaseous ammonia.
Suitable
cyanide sources include: cyanide salts such as, but not limited to, sodium
cyanide, potassium
cyanide and ammonium cyanide; and hydrogen cyanide which may be added in a
continuous-
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addition manner with ammonia to the furfural. The reaction may be carried out
in a protic
solvent or reaction medium such as water or an alcohol, or mixtures of water
and an alcohol
such as, for example, water-methanol or water-ethanol, or mixtures of water
with a polar,
water soluble organic solvent such as, for example, tetrahydrofuran, DMSO,
dioxanc and
acetonitrile, or mixtures thereof Alternatively, this reaction (Step a) may be
carried out in a
2-phase solvent system consisting of water and at least one water immiscible
solvent selected
from, but not limited to, diethyl ether, methyl t-butyl ether (MTBE), ethyl
acetate, methylene
chloride, 2-methyltetrahydrofuran (2-MeTHF), toluene and xylene. Such a
reaction has been
described in WO Application 2000049008, page 55. The present reaction is
typically
conducted with agitation sufficient to maintain an essentially uniform mixture
of the
reactants. A typical reaction generally may require from about 1 to about 50
hours to proceed
to completion. Such a reaction may be conducted at temperatures between about
0 C and
about 50 C, or preferably at temperatures between about 0 C and about 30 C.
After the
reaction is complete, the amino(furan-2-yl)acetonitrile of Formula C may be
recovered by
employing standard isolation and purification techniques or it may be directly
converted to
the compound of Formula D without discreet isolation of the product of Formula
C. It may be
preferable to directly convert the product of Formula C into the salt of
Formula D rather than
storing it for extended periods.
[0012] In Step b of the sequence of reactions to prepare the compound of
Formula D,
at least one equivalent of a mineral acid is added to the intermediate
amino(furan-2-
ypacetonitrile product of Formula C dissolved in a water immiscible solvent
such as, for
example, diethyl ether, MTBE, ethyl acetate, 2-MeTHF, toluene, xylenc, or
mixtures thereof,
to provide the desired cyano(furan-2-yl)methanaminium salt of Formula D.
Suitable mineral
acids may include, but are not limited to, hydrobromic acid (HBr), nitric acid
(HNO3),
sulfuric acid (H2504), and phosphoric acid (H3PO4). The present reaction may
be conducted
at temperatures of from about 0 C to about 25 C. After the reaction is
complete the desired
product is recovered by employing standard isolation and purification
techniques.
[0013] In the bromination/rearrangement reaction (Scheme I, Step c), the
cyano(furan-2-yl)methanaminium salt of Formula D is reacted with a brominating
agent to
provide the brominatedirearrangement product of Formula A. The starting
material of
Formula D as the bromide salt, for example, may be treated with a suitable
brominating agent
such as bromine, 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide. From
about 3
to about 6 molar equivalents of the brominating agent may be used. The
reaction is
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preferably conducted using about 3-5 molar equivalents of bromine and the
bromide salt of
the compound of Formula D (X = Br). It is often convenient to use an excess of
the
brominating agent such as a 5%, 10% or 15% molar excess, to insure the
reaction proceeds to
completion. The reaction is preferably carried out in a protic solvent or
reaction medium
such as water, or mixtures of water and a water soluble, organic solvent such
as, for example,
methanol,
Br
NH3+ XI OH
-
bromination
(flYCN
A
ethanol, tetrahydrofuran, dioxane or acetonitrile. The temperature at which
the reaction is
conducted is between about 0 C and about 60 C and preferably between about 0
C and
about 40 C. Upon completion of the addition of the brominating agent, the
reaction mixture
may be allowed to stir at room temperature for 10-48 hours. Optionally, the
reaction time
may be shortened by adding a base, such as, for example, 2-4 molar equivalents
of sodium
acetate, to the reaction. Optionally, after addition of the brominating agent
is complete, the
reaction may be heated at 30-60 C to complete conversion to the product of
Formula A.
After the reaction is complete the desired product is recovered by employing
standard
isolation and purification techniques.
[0014] An embodiment of the present disclosure involves the preparation of
the
compound of Formula A in a "one-pot" process from furfural. In such a process
all reaction
steps may be conducted in a single vessel whereby the reactants and reagents
are sequentially
added to the vessel and then, after completion of chemical steps a and c, an
isolation
operation is conducted to isolate the product of Formula A. Using the chemical
reactants and
reagents described herein, a cyanide source, an ammonium source and furfural
are combined
together in a reaction vessel with a solvent and sufficiently agitated at a
suitable temperature
and
Br
0
c
BrNCN
A
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for a suitable time to produce the amino(furan-2-yl)acetonitrile product of
Formula C. The
resulting reaction mixture containing the product of Formula C is then treated
with a
brominating agent, such as bromine, optionally using a base, and utilizing
suitable reaction
conditions (time, temperature and/or solvent) as described herein to provide
the product of
Formula A. The product of Formula A is then recovered from the reaction
mixture and
purified as needed by employing standard isolation and purification
techniques.
[0015] Another embodiment of the present disclosure involves preparation of
the
compound of Formula A by a process referred to herein as the biphasic process.
"Biphasic
process" as used herein refers to a process that employs a 2-phase solvent
system. As such, a
2-phase solvent system for the Strecker synthesis of the a-aminoacetonitrile
of Formula C
was used employing the conditions, chemical reactants and reagents described
herein. Use of
the 2-phase solvent system, which includes water and a water-immiscible
organic solvent,
allows for easy separation of water soluble salts present after the Strecker
reaction (i.e.,
cyanide and acetate salts). The a-aminoacetonitrile product remaining in the
organic solvent
is then extracted into an aqueous hydrobromic acid (HBr) solution by formation
of the
corresponding water soluble HBr salt (compound of Formula D; X = Br).
Treatment of the
resulting aqueous solution of the HBr salt of the ot-aminoacetonitrile with
bromine affords
the product of Formula A. The product of Formula A is then recovered from the
final reaction
mixture and purified as needed by employing standard isolation and
purification techniques.
The biphasic process may be conducted at temperatures between about 0 C and
about 50 C
or preferably between about 15 C and about 35 C.
[0016] Another embodiment of the present disclosure involves the
preparation of the
compound of Formula A in a process comprising two chemical steps (i.e, the two-
step
process) from the cyano(furan-2-yl)methanaminium salt of Formula D, wherein X
is as
described herein. In such a process, the compound of Formula D is first
reacted with from
about 1 to about 2 molar equivalents of a brominating agent to provide the 3-
hydroxy-
picolinonitrile product of Formula J. The product of Formula J is then
recovered by
employing standard isolation and purification techniques and is then treated
with from about
2 to about 3 molar equivalents of the brominating agent to furnish the product
of Formula A.
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Br
NH3+ X-
0 Br2
r..LCNI -0- _______________________________ =
BrN
CN CN
J Br2 / A
HOH
Dr I
4- and/or 6-Br intermediate
The two-step process may be conducted using bromine and the bromide salt of
the compound
of Formula D (X = Br). It is often convenient to use an excess of the
brominating agent such
as a 5%, 10% or 15% molar excess, to insure the individual reactions proceed
to completion.
There may be small amounts of the intermediate mono-brominated products (i.e.,
4-bromo-
and/or 6-bromo-3-hydroxypicolinonitrile) present in the isolated product of
Formula A. The
reactions for the 2-step process may be carried out in a protic solvent or
reaction medium
such as water, or mixtures of water and a water soluble, organic solvent such
as, for example,
methanol, ethanol, tetrahydrofuran, dioxane or acetonitrile. The temperature
at which the
reactions may be conducted are between about 0 C and about 75 C. Upon
completion of the
addition of the brominating agent, the reaction mixture may be allowed to stir
at room
temperature for 0-48 hours. Optionally, the conversion of the compound of
Formula J to the
compound of Formula A with a brominating agent may be conducted with an added
base
such as, for example, 2-4 molar equivalents of sodium acetate. After the
reactions are
complete the desired product is recovered by employing standard isolation and
purification
techniques.
B. Preparation of Compound of Formula H
[0017] The chemical steps d, e and f may be performed as depicted in Scheme
II in
two different sequences to prepare the 4-alkoxy-3-hydroxypicolinic acid of
Formula H. In the
substitution reaction to replace the 4-bromo group of the compound of Formula
A with an
alkoxy group (Step d), use of an alkali metal alkoxide of formula MOR1 (M is
an alkali
metal; RI- is a C,-C3 alkyl) produces the 4-alkoxy-6-bromo-3-
hydroxypicolinonitrile of
Formula F. At least 2 equivalents, and preferably 2-5 equivalents, of the
alkali metal alkoxide
are used in this reaction. Typical alkali metal alkoxides useful in this
reaction include sodium
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Scheme II
OR1
OH
OR1 OR1
BrNCO2H ."\46.,
OH
A -11.. OR1
Br NCN N-CO2H
OH
CN
or potassium, methoxide, ethoxide, 1-propoxide or 2-propoxide. The reaction
may be carried
out in a protic solvent or reaction medium such as methanol (for methoxide),
ethanol (for
Br OR1
MORI
Br "N CN BrNCN
A
ethoxide), 1-propanol (for 1-propoxide) or 2-propanol (for 2-propoxide), or
mixtures of
methanol, ethanol, 1-propanol or 2-propanol with a polar, aprotic co-solvent
such as DMSO,
DMF, sulfolane or NMP. The reaction may also be conducted with an alkali metal
alkoxide
in one or more of the polar, aprotic solvents in the absence of an alcohol co-
solvent. The
temperature at which the reaction is conducted is between about 20 C and
about 150 C,
preferably between about about 40 C and about 100 C. The substitution
reaction generally
requires from about 1 to about 48 hours to proceed to completion and may be
conducted
under pressure in a sealed vessel to prevent the loss of volatile solvents.
After the reaction is
complete, the desired product is recovered by employing standard isolation and
purification
techniques.
[0018] In some embodiments the preparation of the compound of Formula F
from the
compound of Formula A may be conducted by employing solvent mixtures including
at least
one of a protic solvent and a polar aprotic solvent whereby the volume percent
(vol%) ratio
of the protic solvent to the polar aprotic solvent in the total solvent
mixture ranges from about
100:0 to about 0:100. In some embodiments the volume percent (vol%) ratio of
the protic
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solvent to the polar aprotic solvent in the total solvent mixture is 80-100
vol% protic solvent
to 0-20 vol% polar aprotic solvent, 60-80 vol% protic solvent to 20-40 vol%
polar aprotic
solvent, 40-60 vol% protic solvent to 40-60 vol% polar aprotic solvent, 20-40
vol% protic
solvent to 60-80 vol% polar aprotic solvent, or 0-20 vol% protic solvent to 80-
100 vol%
polar aprotic solvent. Preferable volume percent (vol%) ratios of the protic
solvent to the
polar aprotic solvent are from about 0.01-10 vol% protic solvent to about 90-
99.99 vol%
polar aprotic solvent. In some embodiments the solvent mixtures used to
prepare the
compound of Formula F = CH3) from the compound of Formula A are methanol
and
DMSO, methanol and DMF, methanol and sulfolane, or methanol and NMP.
[0019] In the hydrolysis reaction of the nitrile group of the 4-alkoxy-3-
hydroxypicolino- nitriles of Formulas F and Ito produce the 4-alkoxy-3-
hydroxypicolinic
acids of Formulas G and H, respectively (Steps e in Scheme II), the starting
picolinonitriles
are typically suspended in a strong, aqueous mineral acid reaction medium and
heated for a
period of time at elevated temperature with good mixing. Strong mineral acids
useful in the
hydrolysis reaction include sulfuric acid, phosphoric acid, hydrochloric acid
and hydrobromic
acid. Preferred, strong mineral acid reaction mediums include aqueous sulfuric
acid mixtures
such as about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55%,
about 60%, about 65%, about 70%, about 75% or about 80% sulfuric acid in water
on a
weight basis. Most preferably, from about 25% to about 70% sulfuric acid in
water may be
used. The temperature at which the hydrolysis reaction may be conducted is
usually between
about 75 C and about 150 C and preferably between about 80 C and about 120
C. The
hydrolysis reaction generally requires from about 8 to about 48 hours,
preferably from about
8 to about 36 hours, to reach completion. After the reaction is complete, the
desired product
OR1 OR1
H+
(H or Br) H20'¨'NCN (H or Br)N"/--"CO2H
is recovered by cooling and slowly pouring the reaction mixture into cold
water and
employing standard isolation and purification techniques.
[0020] In some embodiments, the hydrolysis reaction of the nitrile group of
the 4-
alkoxy-3-hydroxypicolinonitriles of Formulas F and Ito produce the 4-alkoxy-3-
hydroxypicolinic acids of Formulas G and H, respectively (Steps e in Scheme
II), the starting
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81802149
picolinonitriles are suspended in an aqueous reaction medium containing a
strong base, such
as an hydroxide of an alkali or alkaline earth metal, and heated for a period
of time at
elevated temperature with good mixing. Strong bases for use in the hydrolysis
of the
picolinonitriles include sodium hydroxide and potassium hydroxide. The
concentration of
the strong base used in the hydrolysis of the picolinonitriles may range from
about 10 to
about 40 weight percent (wt %), from about 15 to about 40 wt %, from about 20
to about 40
wt %, from about 30 to about 40 wt %, or from about 15 to about 25 wt%. The
molar
equivalent ratio of strong base to the nitrile starting material for the
hydrolysis reaction may
range from about 3:1 to about 10:1, preferably from about 4:1 to about 7:1.
The temperature
at which the strong base hydrolysis reaction may be conducted is usually
between about 75
C and about 150 C and preferably between about 80 C and about 120 C. The
strong base
hydrolysis reaction generally requires from about 8 to about 48 hours,
preferably from about
8 to about 36 hours, to reach completion. After the hydrolysis reaction is
complete, the
desired product may be isolated by acidifying the reaction mixture and
employing standard
isolation and purification techniques.
[0021] Removal of the bromo group from the 6-position of the compound of
Formula
F or the compound of Formula G, to produce the reduced products of Formulas I
and H,
respectively (Steps fin Scheme II), may be achieved by: (1) catalytic
reduction using a
hydrogen source and a transition metal catalyst, or (2) reduction with a metal
such as zinc
and a base such as potassium hydroxide or sodium hydroxide.
[0022] In the catalytic reduction with hydrogen, suitable hydrogen
sources include
hydrogen gas or hydrogen transfer reagents such as ammonium, potassium or
sodium
formate. Suitable transition metal catalysts include, but are not limited to,
palladium on
carbon (Pd/C) and Raney' nickel (Ra/Ni). These catalysts may be used at levels
from about
0.01% to about 10% on a weight basis of the metal to the bromopyridine
substrate.
Exemplary solvents for use in this reaction include methanol, ethanol,
isopropanol, ethyl
acetate, and acetic acid. A soluble base such as, for example, triethylamine
is normally used
in the catalytic reduction with hydrogen.
OR1 OR1
H2 / catalyst
Br N or
(CN or CO2H) Zn / aq. base N (ON or CO2H)
F, G I, H
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From about 2 to about 4 molar equivalents of the soluble base are normally
used. When
hydrogen gas is used as the hydrogen source, the reduction reaction may be
conducted under
an atmospheric pressure of hydrogen gas, or at elevated pressures of hydrogen
gas such as 10,
20, 30, 40, 50, 60, 70, 80, 90, 100 pounds or more, per square inch (psi)
above atmospheric
pressure, or incremental hydrogen gas pressures between these values. It is
preferable to use
the catalytic reduction chemistry for the reduction of the 6-bromopicolinic
acid of Formula G
to produce the picolinic acid of Formula H. After the catalytic reduction
reaction is complete,
the desired product is recovered by employing standard isolation and
purification techniques.
[0023] In the reduction of compounds of Formulas F and G using a metal such
as
zinc, the bromopyridinc substrate (F, G) is dissolved in an aqueous basic
solvent medium and
then treated with zinc metal. From about 1 to about 4 molar equivalents of
zinc metal (i.e.,
Zn dust, Zn powder, or a high surface area Zn solid), preferably 1-3 molar
equivalents, may
be used. The reduction is normally conducted in an aqueous solvent medium of
water
containing a metal hydroxide such as potassium or sodium hydroxide, where the
concentration of the metal hydroxide in water may range from about 10 weight %
to about 30
weight %. The reaction may be conducted at a temperature from about 10 C to
about 60 C,
preferably from about 20 C to about 55 C, for a period of about 5 to about
36 hours. It is
preferred to use the metal reduction chemistry (i.e., Zn/metal hydroxide) for
the reduction of
the 6-bromopicolinonitrile of Formula F to produce the picolinonitrile of
Formula I. After the
metal reduction reaction is complete, the desired product is recovered by
using a mineral or
organic acid workup and then employing standard isolation and purification
techniques.
[0024] In one embodiment, the reductive removal of the bromo group and
hydrolysis
of the nitrile group of the compound of Formula F to produce the compound of
Formula H
can be conducted in a one-pot process using zinc metal (i.e., Zn dust, Zn
powder, or a high
surface area Zn solid) and potassium hydroxide at elevated temperature. The
temperature at
which the one-pot process may be conducted is usually between about 75 C and
about 125
C and preferably between about 80 C and about 100 C. After the reaction is
complete, the
desired product may be isolated by acidifying the reaction mixture and
employing standard
isolation and purification techniques.
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OR1 OR1
Zn / KOH OH
BrN CN H20 ..1\1-"COOH
[0025] The products obtained by any of these processes, can be recovered by
conventional means, such as evaporation, filtration or extraction, and can be
purified by
standard procedures, such as by recrystallization or chromatography.
[0026] The following examples are presented to illustrate the disclosure.
Examples
[0027] Example la. Cyano(furan-2-yl)methanaminium bromide
0 1 NH40Ac NH3+ Br-
KCN, Me0H o 0 -pp. ...r(===CN
2 HBr
[0028] To a magnetically stirred suspension of potassium cyanide (29.3 g,
450 mmol)
and ammonium acetate (116 g, 1500 mmol) in methanol (200 mL) was added furan-2-
carbaldehyde (28.8 g, 300 mmol) at 0-5 C. The reaction mixture was stirred at
0-5 C for 40-
50 hours. After the reaction was complete as indicated by HPLC analysis, the
reaction
mixture was diluted with CH2C12 (300 mL) and 5% NaHCO3 (300 mL). The aqueous
layer
was extracted with additional CH2C12 (4 x 150 mL). The organic layers were
combined and
concentrated under vacuum with Et0Ac. The resulting residual solution was
dissolved in
additional Et0Ac (600 mL) and cooled to 5 C. A solution of 33% HBr (66.1 g,
270 mmol)
in acetic acid was charged slowly to the Et0Ac solution to precipitate a
solid. The solid was
filtered and washed with Et0Ac. The collected solid was dried in air at room
temperature to
give cyano(furan-2-yl)methanaminium bromide (47 g) in 77% yield: 1H NMR (400
MHz,
DMSO-d6) 6 9.39 (s, 3H), 7.94 (dd, J= 1.9, 0.8 Hz, 1H), 6.80 (dt, J= 3.4, 0.7
Hz, IH), 6.63
(ddõI = 3.4, 1.9 Hz, 1H), 6.29 (d, J= 1.8 Hz, 1H); 13C NMR (101 MHz, DMSO-d6)
6 145.60,
142.13, 114.28, 112.43, 111.53, 37.54; HBr salt HRMS-ESI (m/z) calc'd for
[C6H6N20]
122.048 found, 123.055 [M+H] ; m.p. decomposed >120 C.
[0029] Example lb. Cyano(furan-2-yemethanaminium bromide
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0 1 NH4CI, NaCN NH3' Br-
MTBE-water 0
H J.
2 HBr
[0030] To a magnetically stirred suspension of ammoniun chloride (25.03 g,
468
mmol) in MTBE (250 mL) was added furan-2-carbaldehyde (28.8 g, 300 mmol) and a
solution of sodium cyanide (17.20 g, 351 mmol) in water (80 mL) at room
temperature. The
reaction mixture was stirred at room temperature for 15 hours. After the
reaction was
complete, the aqueous layer was removed. The organic layer was washed with
saturated
NaHCO3 solution ( 2x100 mL). The organic layer was dried over Na2SO4 and
filtered. The
resulting filtrate was cooled to 5 C and a solution of 33% HBr (57.4 g, 234
mmol) in acetic
acid was charged slowly into the solution to precipitate a solid. The solid
was filtered and
washed with MTBE. The collected solid was dried in air at room temperature to
give
cyano(furan-2-yl)methanaminium bromide (29 g) in 54% yield. This sample
exhibited similar
spectral properties to the sample prepared in Example la.
[0031] Example I c. 4,6-Dibromo-3-hydroxypicolinonitrile
Br
NH3 + Br Br2 I Na0Ac OH
CN
H20 / Me0H BrNCN
[0032] To a mechanically stirred solution of cyano(furan-2-yOmethanaminium
bromide (143 g, 704 mmol) in water (1408 mL) at 5 C was slowly added Br2 (225
g, 1409
mmol) from a dropping funnel while maintaining the temperature at <15 C.
After a further
10-15 minutes (after bromine addition was complete), sodium acetate (144 g,
1761 mmol) and
methanol (281 mL) were added to the reaction mixture, followed by the dropwise
addition of
a second portion of Br2 (109 mL, 338 g, 2113 mmol) while maintaining the
temperature at
<20 C. The reaction mixture was then stirred overnight at room temperature.
After the
reaction was complete as indicated by HPLC analysis, the reaction mixture was
cooled to 5-
C, and slowly charged with an aqueous solution of 20% NaHS03 (704 mL) while
keeping
the temperature at <20 C. The resulting suspension was stirred for 0.5 hr and
then filtered.
The filter cake was washed with water, dried in air for several hours and then
in a vacuum
oven at 50 C overnight to give 4,6-dibromo-3-hydroxypicolinonitrile (137 g)
as a light
yellow solid in 70% yield: 1H NMR (400 MHz, DMSO-d6) .3 8.28 (s, 1H); 13C NMR
(101
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MHz, DMSO-d6) 6 155.55, 135.72, 129.81, 125.96, 121.61, 114.58; HRMS-ESI (m/z)
calc'd
for [C6H2Br2N20] 275.8534; found, 275.851; mp 183-185 C.
[0033] Example id. 4,6-Dibromo-3-hydroxypicolinonitrile (1-pot process)
Br
0
1. KCN / NH40Ac OH
0
NrkH
2. Br2 I H20 BrNCN
[0034] To a magnetically stirred suspension of potassium cyanide (7.16 g,
110 mmol)
and ammonium acetate (10.02 g, 130 mmol) in methanol (50 mL) was added furan-2-
carbaldehyde (9.61 g, 100 mmol) at room temperature. The reaction mixture was
stirred at
room temperature overnight. After the reaction was complete as indicated by
HPLC analysis,
the reaction mixture was diluted with water (100 mL) and cooled to 5 C.
Bromine (80 g,
500 mmol) was charged slowly to the reaction while maintaining the temperature
at <20 C.
The reaction mixture was warmed and stirred overnight at room temperature.
After the
reaction was complete as indicated by HPLC analysis, the reaction mixture was
cooled to 5-
C, and an aqueous solution of 10% NaHS03 (100 mL) was slowly charged while
maintaining the temperature at <20 C. The resulting suspension was stirred
for 0.5 hr and
then filtered. The filter cake was washed with water, dried in air for several
hours and then in
a vacuum oven at 50 C overnight to give 4,6-dibromo-3-hydroxypicolinonitrile
(8 g) as a
brown solid in 28% yield. IH NMR (400 MHz, DMSO-d6) 6 11.67 (s, 1H), 8.19 (dd,
J= 4.4,
1.3 Hz, 1H), 7.56 (dd, J= 8.6, 4.4 Hz, 1H), 7.47 (dd, J= 8.6, 1.4 Hz, 1H); 1-
3C NMR (101
MHz, DMSO) 6 157.69, 142.01, 128.86, 124.41, 120.31, 115.99.
[0035] Example le. 4,6-Dibromo-3-hydroxypicolinonitrile (two step process)
Br
NH3+ Br Br2 aOH Br2 / Na0Ac OH
\ CN H20
N CN H20 / Me0H
Br'sNCN
[0036] To a mechanically stirred solution of cyano(furan-2-yl)methanaminium
bromide (10.15 g, 50 mmol) in water (100 mL) at 5 C was slowly added Br2
(15.98 g, 100
mmol) from a dropping funnel while maintaining the temperature at <15 C.
After a further
30 minutes the reaction mixture was slowly charged with an aqueous solution of
20%
NaHS03 (50 mL) while keeping the temperature at <20 C. The resulting
suspension was
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stirred for 0.5 hr and then filtered. The filter cake was washed with water,
dried in air for
several hours and then in a vacuum oven at 50 C overnight to give 3-
hydroxypicolinonitrile
(2.4 g) as a brown solid in 40% yield: 1H NMR (400 MHz, DMSO-d6) 6 11.67 (s,
1H), 8.19
(dd, J= 4.4, 1.3 Hz, 1H), 7.56 (dd, J= 8.6, 4.4 Hz, 1H), 7.47 (dd, J= 8.6, 1.4
Hz, 1H); 13C
NMR (101 MHz, DMSO) 6 157.69, 142.01, 128.86, 124.41, 120.31, 115.99; mp 203
C.
[0037] To a mechanically stirred solution of 3-hydroxypicolinonitrile
(12.01 g, 100
mmol) and sodium acetate (16.4 g, 200 mmol) in water (150 mL) and methanol (50
mL) at 5
C was slowly added Br2 (47.9 g, 300 mmol) from a dropping funnel while
maintaining the
temperature at <20 C. The reaction mixture was then stirred overnight at room
temperature.
After the reaction was complete as indicated by HPLC analysis, the reaction
mixture was
cooled to 5-10 C, and slowly charged with an aqueous solution of 20% NaHS03
(100 mL)
while keeping the temperature at <20 C. The resulting suspension was stirred
for 0.5 hr and
then filtered. The filter cake was washed with water, dried in air for several
hours and then in
a vacuum oven at 50 C overnight to give 4,6-dibromo-3-hydroxypicolinonitrile
(27 g) as a
light yellow solid in 97% yield. The sample exhibited similar spectral
properties to other
samples of 4,6-dibromo-3-hydroxypicolinonitrile prepared herein.
[0038] Example If. 4,6-Dibromo-3-hydroxypicolinonitrile (biphasic process)
Br
o
0 1. KCN / NH40Ac OH
.
2. HBr / H20
BrCN
3 Br2 / H20
[0039] To a magnetically stirred suspension of potassium cyanide (103 g,
1575
mmol) and ammonium acetate (347 g, 4500 mmol) in ethyl acetate (1500 mL) and
water (375
mL) was added furan-2-carbaldehyde (144 g, 1500 mmol) at room temperature. The
reaction
mixture was stirred at room temperature overnight. After the reaction was
complete as
indicated by 1H NMR analysis, the reaction mixture was diluted with 20% Na2CO3
(750 mL).
After phase separation, the organic layer was washed with a saturated solution
of aqueous
NaCl (375 mL). The organic layer containing 2-amino-2-(furan-2-yl)acetonitrile
was
extracted with 1953 naL of 3.7% aqueous hydrobromic acid (HBr) solution. The
organic layer
was extracted with additional water (2 x 200 mL). The combined aqueous layers
were cooled
to 5 C and bromine (959 g, 6000 mmol) was charged slowly via use of a
peristaltic pump and
Teflon tubing to the HBr solution while maintaining the temperature at <20 C.
The reaction
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mixture was then warmed and stirred overnight at 25 'C. After the reaction was
complete, as
indicated by 1H NMR analysis, the reaction mixture was cooled to 5-10 `V, and
then all
aqueous solution of 40% NaHS03 (400 mL) was slowly charged while maintaining
the
temperature at <20 C. The resulting suspension was stirred for 0.5 hr and
then filtered. The
filter cake was washed with water (2 x 200 mL), and dried at ambient
temperature in the air to
give 4,6-dibromo-3-hydroxypicolinonitrile (251 g) as a tan solid in 60% yield.
1H NMR (400
MHz, DMSO-d6) 6 8.28 (s, 1H); 13C NMR (101 MHz, DMSO-d6) 6 155.57, 135.72,
129.77,
125.97, 121.60, 114.59. HRMS-ES1 (m/z) calc'd for [C6H2Br7N )0] , 275.8534;
found,
275.8510. The tan solid was found to contain about 94.5 % of 4,6-dibromo-3-
hydroxypicolinonitrile and less than about 6% of a mono-brominated
intermediate product
which was tentatively assigned as either 4-bromo-3-hydroxypicolinonitrile or 6-
bromo-3-
hydroxypicolinonitrile as determined by MS analysis.
[0040] Example 1g. 4,6-Dibromo-3-hydroxypicolinonitrile (biphasic process)
Br
0 1. KCN / NH40Ac OH
___________________________________ =
C)7)(
2 HBr / H20 Br'
ON
3 Br2 / H20
[0041] A 30 L jacketed glass reactor was charged with ammonium acetate
(3371 g,
43.73 mol), ethyl acetate (13,144 g), potassium cyanide (1,000 g, 15.38 mol),
and then water
(1819 g). The agitation was turned on to 150 rpm, and then furfural (1,398 g,
14.56 mol) was
fed into the reactor via a pump at room temperature. The reaction was allowed
to stir
overnight at room temperature, at which point the reaction was >97 % complete
as
determined by 1H NMR analysis. A solution of 16 % sodium carbonate in water
(7300 g) was
added to the reaction mixture. The reaction mixture was allowed to stir for 1
h. After
settling, the aqueous phase was removed, and then the organic phase was washed
with
saturated brine (5677 g, 23%). After removing the brine, the organic solution
was transferred
via pump to a 50 L jacketed glass reactor which contained DI water (8896 g).
48 % aqueous
HBr (2466g, 14.6 mol) was diluted with DI water (5668 grams) and the resulting
HBr
solution was then pumped into the 50 L reactor with the agitation at 150 rpm
at room
temperature. After allowing the mixture to stir for 1 hour, the phases were
allowed to
separate for 45 minutes. The aqueous phase was drained into two 5 gallon
carboys. The
organic phase was then washed 2 times with about 2,000 gram of DI water. The
DI water
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washes were placed in the carboys. The organic phase was discarded and then
the 50 L
reactor was washed with 500 mL of ethyl acetate and 500 mL of DI water. The
aqueous
phase (24,536 grams) in the two carboys was transferred back to the 50 L
reactor, and then
the residual HBr salt in the carboys was washed into reactor with a total of
1945 grams of DI
water. The aqueous phase in the reactor was then cooled to about 0 C and
allowed to mix
overnight. Bromine (9311 grams, 56.1 mol) was then added to the reaction over
45 minutes
(initial temperature of about 0 C), which resulted in a temperature rise to
25 C. During the
bromine addition, a material precipitated from solution and then re-dissolved.
About 1 h after
the feed of bromine was completed, solids began to reform in the solution. The
reaction was
then heated at 35 C for about 24 h. The reaction was then cooled to <10 C,
and then 40%
aqueous sodium bisulfite (3757 g) was added to quench the excess bromine. The
solids were
collected by filtration and washed with DI water (5L) until the wash liquid
was colorless.
The resulting wet cake was allowed to dry in glass trays until no further
weight loss was
observed, which resulted in 2590 grams of a free flowing tan powder. 1H NMR
assay
indicated that the solid was 97.8 wt % 4,6-dibromo-3-hydroxy-picolinonitrile.
The yield
based on the assay was 62.6 %. 1H NMR (400 MHz, DMSO-d6) 6 8.28 (s, 1H), 7.75
(d, J =
8 Hz, 0.03H), 7.43 (d, J = 8 Hz, 0.03H);13C NMR (101 MHz, DMSO) 6 155.47,
135.68,
129.86, 125.88, 125.88, 121.63, 114.50. HRMS (m/z) Positive Ion mode [M+1]
calcd for
[C6H3Br2N20]+ 276.8607; found 276.8609.
[0042] Example lh. 3-Hydroxypicolinonitrile (biphasic process)
0 1 KCN / NH40Ac
\ 0 /
2. HBr / H20
3 Br2 I H20
[0043] To an inerted 6L straight-walled jacketed reactor was added 346
grams of
ammonium acetate (4500 mmol), 1500 mL of ethyl acetate (Et0Ac), 300 mL of DI
water, and
102.5 grams of potassium cyanide (KCN, 1574 mmol). The KCN jar and addition
funnel
were then rinsed with about 75 mL of water to wash any residual KCN into the
reactor. The
reaction vessel was closed, cooled to 15 C and the agitation was then set to
260
rpm. Furfural (144 g, 1500 mmol) was then added to the reactor via syringe
over 5
minutes. The temperature in the reactor increased from about 15 C to 22 C.
The reaction
was allowed to stir overnight (22 C). The agitation was turned off to allow
the phases to be
separated. The organic phase was then sampled for 1H NMR analysis. The
reaction was
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shown to be >99 % converted to the desired product. With agitation (250 rpm),
750 mL of 20
% aqueous sodium carbonate was added to the reactor and allowed to stir for 10
minutes. The
aqueous phase containing the sodium carbonate solution was removed and then
the remaining
organic phase was washed with 400 mL of saturated brine. 170 mL of aqueous 48
% HBr (1
equiv., 1345 mmol) diluted in about 1300 ml of DI water was added to the
reactor containing
the organic phase. The reactor containing the aqueous HBr-organic phase was
mixed (250
rpm) for 15 minutes. After settling, the aqueous layer was drained into a 5 L
receiving vessel.
The organic layer was then washed with an additional 250 mL of DI water which
was also
drained into the 5 L vessel. The reactor was then emptied and rinsed with 300
mL of Et0Ac.
The aqueous layer in the 5 L vessel was then vacuum transferred back up to the
5 L straight-
walled reactor. The 5L receiving vessel was washed with 200 mL of water which
was also
added to the reactor. The contents of the reactor were then agitated, cooled
to 0 C and then
bromine (240 g, 1500 mmol) was added via a Teflon line through a peristaltic
pump over 30
minutes, which led to a temperature rise to 19 C and the formation of a
precipitate. The
reaction was allowed to stir overnight at room temperature. 40 % aqueous
sodium bisulfite
(250 mL) was then added slowly to the reaction to maintain a temp <40 C.
After the
bromine was quenched, the solids were collected on a frit and washed with
water and dried to
yield 3-hydroxypicolinonitrile in 47 % yield (85 g) as a red crystalline
solid. 1H NMR (400
MHz, DMSO-d6) 6 11.67 (s, 1H), 8.21 (dd, J= 4.4, 1.4 Hz, 1H), 7.57 (dd, J=
8.6, 4.4 Hz,
1H), 7.50 (dd, J= 8.6, 1.4 Hz, 1H) "C NMR (101 MHz, DMS0) 6 157.66, 141.92,
128.72,
124.35, 120.34, 115.97. HRMS (m/z) Positive Ion mode [M+1] calcd for
[C6H5N2O]f
121.0397; found 121.0400
[0044] Example 2a. 6-Bromo-4-methoxy-3-hydroxypicolinonitrile
Br OM e
Na0Me
BrNCN Me0H/DMS0 BrNCN
[0045] To a magnetically stirred solution of 4,6-dibromo-3-
hydroxypicolinonitrile
(152 g, 547 mmol) in DMS0 (820 mL) was added a 30% Na0Me in Me0H (492 g, 2.73
mol) solution at room temperature. The reaction mixture was warmed to 50-55 C
and stirred
overnight. The reaction mixture was then cooled to 15-20 C, quenched by slow
addition of
1.5N HC1 (1500 mL) to adjust the pH to about 2-3, and then extracted with
CH2C12 (2 x 1000
mL). The combined organic layers were washed with 0.1N HCI (1000 mL) and
concentrated
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to ca. 500 ml volume, charged with 100 mL of acetonitrile (ACN), and finally
concentrated
to dryness. The crude product obtained was washed with 0.1N HC1 (1000 mL) and
filtered.
The filter cake was washed with water, dried in air for several hours and then
in a vacuum
oven at 50 C overnight to give 6-bromo-3-hydroxy-4-methoxypicolinonitrile (83
g) in 66%
yield as a brown solid: 1H NMR (400 MHz, DMSO-d6) 6 11.64 (s, 1H), 7.48 (s,
1H), 3.97 (s,
3H); 13C NMR (101 MHz, DMSO-d6) 6156.54, 149.35, 131.02, 118.54, 114.91,
114.57,
57.20; HRMS-ESI (m/z) calc'd for [C7H5BrN207], 227.9533; found, 227.9534; m.p.
168 C.
The aqueous filtrate was extracted with CH2C12 (twice). The organic layers
were combined
and concentrated with ACN as described herein. The crude solid was dissolved
in ACN (50
mL) and added slowly into 0.1N HCl (400 mL) at room temperature. The
precipitated solid
was stirred for lh and filtered. The filter cake was washed with water and
dried to give
additional 6-bromo-3-hydroxy-4-methoxypicolinonitrile (13 g) in 10% yield.
[0046] Example 2b. 6-Bromo-4-methoxy-3-hydroxypicolinonitrile
Br OMe
OH Na0Me
BrNCN Me0H/DMS0 BrNCN
[0047] 4,6-dibromo-hydroxypicolinonitrile (500 grams, 1806 mmol) was
dissolved in
a mixture of 500 mL of anhydrous DMSO and 20 mL of anhydrous Me0H at room
temperature under an inert atmosphere. Sodium methoxide (250 grams, 4606 mmol)
and
500 mL of anhydrous DMSO were then charged to a 5-L, 4-neck reaction flask
which had
been purged with nitrogen. The reaction flask was outfitted with a condenser
(w/N2 line),
thermal well, mechanical stirrer and a septum (with a 1/8" feed line). The
solution of the 4,6-
dibromo-hydroxypicolinonitrile in DMSO-Me0H was then fed to the reaction flask
at a rate
of 15-20 g per minute via a peristaltic pump through the 1/8" Teflon tubing.
When the
reaction temperature reached 55 C, a cold water bath was placed around the
flask. The
reaction was maintained between 50 and 55 C during the feed. The reaction was
then
maintained at around 54 C for 1.5 h after addition was complete. After
determining the
reaction was complete by 1H NMR analysis, the reaction mixture was cooled to
<30 C with
an ice bath. At 30 C, 2 L of water were added to the reaction mixture which
caused the
solution to warm to >40 C. The reaction mixture was cooled to 30 C, and then
10 N
sulfuric acid was added via an addition funnel until the pH was around 2.5,
which resulted
in the precipitation of a white solid. At pH 2.5, the reaction was allowed to
stir for 30-60
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minutes during which time the reaction mixture was cooled to 15 C. The solid
was filtered
and then washed with water until the filtrate was colorless. The solid was
dried in a vacuum
oven at 50 C until the weight remained constant. The solid was a slightly tan
colored powder
(344 g, 83 % yield): : 1H NMR (400 MHz, DMSO-d6) 6 11.64 (s, 1H), 7.48 (s,
1H), 3.97 (s,
3H); 13C NMR (101 MHz, DMSO-d6) 6 156.54, 149.35, 131.02, 118.54, 114.91,
114.57,
57.20.
[0048] Example 2c. 6-Bromo-4-methoxy-3-hydroxypicolinonitrile
Br OMe
Na0Me
Me0H/DMS0
131-/NN'/ON CN
[0049] 25.1 kg of dimethyl sulfoxide (DMSO) was loaded into a glass lined
steel
(GLS) reactor and heated under jacket temperature control set point of 100 C
with a purge of
nitrogen at 4 liter/min at atmospheric pressure for 18 hours. The jacket
temperature was
reduced to 35 C and the DMSO was allowed to cool. 4,6-dibromo-3-
hydroxypicolinonitrile
(8.0 kg, 28.8 mol) was loaded in to the reactor with the vent open and a 1
liter/min nitrogen
purge. The reactor was set to control pressure at 25 mm Hg (actual pressure
controlled at a
nominal pressure of 35 ¨ 60 mm Hg), agitated at 90 rpm and put under master
temperature
control, which utilized the actual reaction mixture, of 30 C. The overhead
heat exchanger,
used to condense methanol, was operated at -5 to -10 C. A 25% by weight sodium
methoxide mixture in methanol (16.51 Kg, 76.4 mol) was pumped into the reactor
over about
30 - 45 minutes. Methanol was continuously stripped from the reaction mixture
and
condensed. After the methoxide had been added, the reaction temperature was
increased to
53 C over 1.5 hours. Approximately 5.5 hours after reaching 52 ¨ 53 C, the
reaction was
sampled and determined to be complete by 1H NMR. The reaction mixture was
cooled
under a jacket control temperature of 35 C and methanol was flushed through
process sample
lines and the sodium methoxide feed addition pump. 25 kg of de-ionized (DI)
water was
added to the reaction mixture and the entire contents transferred to a
stainless steel (SS)
reactor. An additional 25 kg of DI water was loaded into the GLS reactor and
the contents
transferred to the SS reactor. 26.6 kg of a 20% aqueous sulfuric acid mixture
was added to
the basic (pH 13) aqueous reaction product, sodium 6-bromo-2-cyano-4-
methoxypyridin-3-
olate, to result in a pH <2. The neutralized 6-bromo-4-methoxy-3-hydroxy
picolinonitrile
was isolated using a centrifuge. The wetcake was washed using 5 gallons of DI
water that
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was loaded into the SS reactor to flush residual solids to the centrifuge. The
solids were spun
dry under nitrogen in the centrifuge and the vv-etcake was further dried under
a purge of dry
nitrogen until no further weight loss was observed. 5.011 kg of dried 6-bromo-
4-methoxy-3-
hydroxypicolinonitrile was obtained as an off-white solid (76 % yield). 1H NMR
assay of the
material indicated that the product was >99.5 % pure.
[0050] Example 2d. 6-Bromo-4-methoxy-3-hydroxypicolinonitrile
Br OMe
Na0Me
BrNCN DMSO BrNCN
[0051] To a slurry of sodium methoxide (15.2 g, 282 mmol) in 35 mL of
anhydrous
dimethyl sulfoxide (DMSO) was added a solution of 4,6-dibromo-3-
hydroxypicolinonitrile
(30 g, 108 mmol) in anhydrous DMSO (30 mL). The solution was added over 30
minutes
and the reaction mixture was maintained below 55 C during the addition. The
reaction
solution was heated for an additional 1.5 hours after the feed was complete.
The resulting
reaction mixture was cooled to <30 C, and then 120 mL of DI water was added.
The
reaction mixture was allowed to cool to about 25 C. The pH of the reaction
mixture was
adjusted to about 2 with 40 % sulfuric acid, which resulted in the
precipitation of a solid. The
solid were collected by filtration, washed with 75 mL of pH 1.5 sulfuric acid
followed by 25
mL of DI water. The solid was then allowed to dry to yield 20.7 g (83.7 %
yield) of desired
product. 1H NMR (400 MHz, DMSO-d6) 6 11.60 (s, 1H), 7.47 (s, 1H), 3.98 (s,
3H). '3C
NMR (101 MHz, DMSO) 6 156.52, 149.35, 130.99, 118.55, 114.89, 114.52, 57.18.
[0052] Example 2e. 6-Bromo-4-methoxy-3-hydroxypicolinonitrile
OMe
OH
Na0Me
Br N CN Me0H
BrNCN
[0053] To a solution of 4,6-dibromo-3-hydroxypicolinonitrile (1.11 g, 4.0
mmol) in
methanol (7.5 mL) in a 40 mL microwave tube was added a solution of 25 wt%
Na0Me in
Me0H (2.59 g, 12 mmol). The solution was heated at 110 C under microwave
irradiation
for 12 h. The reaction mixture was then cooled to 15-20 C, quenched by slow
addition of 2
M HC1 to adjust the pH to about 4-5. The reaction mixture was concentrated by
rotary
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evaporation. The mixture was purified by flash chromatography on silica gel,
eluting with
methanol/CH2C12 to give 0.53 g (58% yield) of solid (mp = 177-180 'V). 1H NMR
(400
MHz, Methanol-4) 6 7.33 (d, J = 1.0 Hz, 1H), 4.01 (s, 3H). 13C NMR (101 MHz,
Methanol-
di) 6 157.96, 150.91 , 132.58, 119.91 , 115.50, 115.09 , 57.66.
[0054] Example 2f. 6-Bromo-4-etboxy-3-hydroxypicolinonitfile
Br OEt
Na0Et
Et0H/DMS0
Br'NCN
[0055] To a magnetically stirred solution of 4,6-dibromo-3-
hydroxypicolinonitrile
(5.40 g, 19.4 mmol) in DMSO (30 mL) was added a 21% Na0Et in Et0H (31.5 g, 97
mol)
solution at room temperature. The reaction mixture was heated at 55 'V for 18
h. The reaction
mixture was then cooled to 15-20 C and poured into a mixture of 25 mL of
concentrated HC1
and 80 g of ice. A tan precipitate formed. The mixture was extracted into
Et0Ac (4 x 75
mL). The combined organics were washed with water (5 x 100 mL) and then brine.
The
extracts were dried (MgSO4) and rotary evaporated to a tan solid. The solid
was triturated
with 1:1 hexane-ether (3 x 20 mL) and then dried in air to yield a light tan
solid (4.39 g, 93%
yield, nip. = 175-177 C). 1H NMR (400 MHz, DMSO-d6) 6 11.42 (s, 1H), 7.45 (s,
1H),
4.25 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO) 6
155.81,
149.32, 131.15, 118.63, 114.94, 114.87, 65.74, 13.94. HRMS-ESI (m/z) calc'd
for
[C8H7BrN202] , 241.9691; found, 241.9690.
[0056] Example 2g. 6-Bromo-3-hydroxy-4-methoxypicolinic acid
OMe OMe
66% H2SO4
909500BrNCN Br-NCO2H
[0057] To a magnetically stirred solid sample of 6-bromo-3-hydroxy-4-
methoxypicolin- onitrile (88g, 384 mmol) was added 66% H2SO4 (384 mL) at room
temperature. The resulting mixture was warmed and stirred overnight at 90-95
C. After
HPLC indicated the reaction was complete, the reaction mixture was cooled to
30-40 C and
transferred slowly to a flask charged with water (3072 g) to precipitate the
product. The
resulting suspension was stirred for 0.5 hr. The resulting precipitate was
filtered, washed with
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81802149
water, and dried in air overnight to give 6-bromo-3-hydroxy-4-methoxypicolinic
acid (95 g)
as an off-white solid in 100 % yield: IH NMR (400 MHz, DMSO-d6) 6 7.48 (s,
1H), 3.97 (s,
3H); 13C NMR (101 MHz, DMSO-d6) 6 170.12, 156.58, 149.09, 130.19, 129.86,
114.46,
56.79; HRMS-ESI (m/z) [M+H]+ calcd for C7H6BrN04, 246.948; found, 246.948;
m.p. 167-
170 C.
[0058] Example 2h. 6-Bromo-4-ethoxy-3-hydroxypicolinic acid
OEt OEt
).X
OH
'N I CN 66% H2604
Br
_b.
90-95 C ...1.....OH
1
Br"---IV CO2H
[0059] 6-Bromo-4-ethoxy-3-hydroxypicolinonitrile (906 mg, 3.73 mmol) was
added
to 66% H2SO4 (15 mL) at room temperature. The resulting mixture was
magnetically stirred
and heated at 90 C for 17 h, cooled to ambient temperature, and poured into
12 g ice. A
solution of 50% NaOH was added until a tan solid precipitated. The solid was
extracted into
Et0Ac (3 x 25 mL), dried over MgSO4, and rotary evaporated to 923 mg of white
crystalline
solid (94% yield, m.p. = 152¨ 155 C). IHNMR (400 MHz, DMSO-d6) 6 11.5 (br,
1H),
7.36 (s, 1H), 4.19 (q, J= 7.0 Hz, 2H), 1.36 (t, J= 7.0 Hz, 3H). HRMS-ESI (m/z)
[M+H]+
calcd for C8H8BrN04, 260.9637; found, 260.964.
[0060] Example 2i. 3-Hydroxy-4-methoxypicolinic acid
OMe 0 Me
jõ.OH
H2/ 5% Pd/C
I __________________________________ D.-
1
E
Br '1\1 t3N, Et0H CO2H 'N"..0O2H
[0061] Batch 1: To 3-hydroxy-6-bromo-4-methoxypicolinic acid (47.5 g) and
Et0H
(576 mL) in a Parr shaker bottle (2 L) was added triethylamine (40.7 g, 402
mmol). Then
under a nitrogen atmosphere 5% Pd/C (20 g, 9.6 mmol; 5 mol%) was added to the
bottle.
The reaction slurry was placed on a Parr shaker and the bottle placed under
hydrogen gas
(40-45 psi) and shaked. After completion of the reaction as indicated by HPLC
analysis, the
hydrogen gas was removed under vacuum and replaced with nitrogen gas. The
reaction
slurry was filtered through a pad of celitem and the celite pad was washed
with fresh ethanol.
[0062] Batch 2: To 3-hydroxy-6-bromo-4-methoxypicolinic acid (47.5 g) and
Et0H
(576 mL) in a Parr shaker bottle (2 L) was added triethylamine (40.7 g, 402
mmol). Then
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under a nitrogen atmosphere added 5% Pd/C (10 g, 4.8 mmol; 2.5 mol%). The 2"
reaction
was completed as described for the ls`batch. The ethanolic filtrates for the 2
batches were
combined and concentrated to give a solid. The solid was diluted with 0.2N HC1
(400 mL)
to adjust the pH to about 1-2 and the resulting suspension was stirred for 10-
15 minutes at
room temperature. The solid was then collected by filtration, washed with
water and dried in
air for several hours and then in a vacuum oven at 50 0C to give 3-hydroxy-4-
methoxypicolinic acid (55 g) as an off-white solid in 85% yield: 1H NMR (400
MHz,
DMSO-d6) 6 8.04 (d, J= 6.4 Hz, 1H), 7.40 (d, J= 6.5 Hz, 1H), 4.04 (s, 3H); 13C
NMR (101
MHz, DMSO-d6) 6 164.16, 162.03, 152.52, 132.32, 126.57, 109.13, 57.35; HRMS-
ESI (m/z)
calcd for C7H7N04, 169.0379; found, 169.0375; m.p. 219 C.
[0063] Example 2j. 3-Hydroxy-4-ethoxypicolinic acid
OEt OEt
.71x0H H2 / 5% Pd/C
Br 'N CO2H Et3N , Et0H
[0064] To 6-bromo-4-ethoxy-3-hydroxypicolinic acid (739 mg) and Et0H (20
mL) in
a Parr shaker bottle (0.5 L) was added triethylamine (599 mg, 5.92 mmol). 5%
Pd/C (300 mg,
0.141 mmol; 5 mol%) was added to the bottle. The reaction mixture was shaken
under
hydrogen gas (45 psi) for 22 h. The reaction mixture was filtered through a
pad of celite, and
the celite pad was washed with ethanol. The filtrate was rotary evaporated to
a white solid
(1.047 g) which was then slurried in 15 mL of 0.1M HC1 and filtered. Solid was
washed with
mL of 0.1M HC1 and then 5 mL water. Solid was dried in air to give 402 mg (78%
yield,
m.p. = 216-219 C) of off-white powder. 1H NMR showed the presence of 7%
Et3NHC1 in
addition to product resonances. 1H NMR (400 MHz, DMSO-d6) 6 14.4 (br, 1H),
8.01 (d, =
6.4 Hz, 1H), 7.38 (d, J= 6.4 Hz, 1H), 4.32 (q, J= 7.0 Hz, 2H), 1.41 (t, J= 7.0
Hz, 3H).
13C CHI NMR (DMSO-d6. 126 MHz) 6164.33, 161.13, 152.37, 132.44, 126.92,
109.53,
66.02, 14.05. HRMS-ESI (m/z) [M+H]+ calcd for C8H9Bra4, 183.0532; found,
183.0536.
[0065] Example 2k. 3-Hydroxy-4-methoxypicolinonitrile
OM e OM e
Zn / KOH
H
Br N 20
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[0066] A suspension of 6-bromo-3-hydroxy-4-methoxypicolinonitrile (7.5 g,
32.7
mmol), Zn dust (4.28 g, 65.5 mmol) and 20% aqueous KOH (100 mL) was stirred
overnight
at room temperature. After completion of the reaction as indicated by HPLC
analysis, the
reaction mixture was filtered through celitc. The aqueous filtrate was cooled
to 5 C and
adjusted to a pH of about 3-4 with 3N HC1 (-125 mL). The precipitated solid
was filtered,
washed with water and dried in air and then in a vacuum oven at 50 C to give
3-hydroxy-4-
methoxypicolinonitrile (4 g) as a brown solid in 81% yield: 1H NMR (400 MHz,
DMSO-d6)
6 11.12 (s, 1H), 8.08 (d, J= 5.3 Hz, 1H), 7.28 (d, J= 5.3 Hz, 1H), 3.94 (s,
3H); 13C NMR
(101 MHz, DMSO-d6) 6 154.69, 148.59, 143.51, 119.84, 116.07, 110.54, 56.36;
HRMS-ESI
(m/z) calcd for C7H6N202, 150.043; found, 150.0429; m.p. 224 C.
[0067] Example 21. 3-Hydroxy-4-methoxypicolinic acid
OMe OMe
aqueous KOH
NCN 809000
[0068] A 1 L, 3-neck round bottom flask was charged with 125 grams of KOH
(1952
mmol, 88% assay for KOH) and then 400 grams of water. The flask was outfitted
with a
mechanical stirrer, thermal well, and a condenser (w/ N2 inlet). The solution
was mixed until
the KOH dissolved. 3-Hydroxy-4-methoxypicolinonitrile (50 g, 334 mmol) was
then added
to the solution, which did not result in an exotherm. The reaction was heated
to 90 C. After
the reaction was considered complete by NMR analysis (12 II), the reaction
solution was
allowed to cool to ambient temperature and allowed to stand overnight. 12N HC1
was added
until the pH was 2-3, which caused the product to precipitate out of solution.
The solids were
collected by filtration and washed with 10 mL of Me0H and then 10 mL of MTBE.
The
product was allowed to dry overnight and then was placed in the vacuum oven
for 4 hours at
60 C. 49.2 grams of 3-hydroxy -4-methoxy picolinic acid was obtained as an
off-white solid
(87.2% yield); 1H NMR (400 MHz, DMSO-d6) 6 8.04 (d, J= 6.4 Hz, 1H), 7.39 (d,
J= 6.5
Hz, 1H), 4.04 (s, 3H); 13C NMR (101 MHz, DMSO-d6) 6 164.16, 162.03, 152.52,
132.32,
126.57, 109.13, 57.35; HRMS-ESI (m/z) calcd for C7H7N04, 169.0379; found,
169.0375.
[0069] Example 2m. 3-Hydroxy-4-methoxypicolinic acid
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OMe OMe
Zn / KOH
Br'N CN H20 'NCOOH
90 c
[0070] A 1 L, 3-neck round bottom flask with a mechanical stirrer was
charged with
6-bromo-3-hydroxy-4-methoxypicolinonitrile (45.8 g, 200 mmol) and zinc dust
(14.38 g, 220
mmol) in water (200 mL). 45% KOH (125 g, 1000 mmol) was charged slowly at rt.
The
reaction was heated to 90 'C. After the reaction was considered complete by
HPLC analysis
(20 h), the reaction solution was allowed to cool to ambient temperature. The
reaction
mixture was filtered through celite. The filtrate was cooled with an ice bath
and then 12N
HC1 (ca. 90 mL) was added until the pH was 0.9. The solids were collected by
filtration and
washed with 0.1N HC1 and water. The product was allowed to dry overnight and
then was
placed in the vacuum oven overnight at 50 C. 3-hydroxy-4-methoxy picolinic
acid was
obtained as an off-white solid (26.9 g, 80 % yield): 1H NMR (400 MHz, DMSO-d6)
6 8.04
(d, J= 6.4 Hz, 1H), 7.39 (d, J= 6.5 Hz, 1H), 4.04 (s, 3H); 13C NMR (101 MHz,
DMSO-d6) 6
164.16, 162.03, 152.52, 132.32, 126.57, 109.13, 57.35; HRMS-ESI (m/z) calcd
for C7H7N04,
169.0379; found, 169.0375.
[0071] Example 2n. 3-Hydroxy-4-methoxypicolinic acid
OMe OMe
40% H2SO4
NCN 9000
[0072] To a magnetically stirred solid of 3-hydroxy-6-bromo-4-
methoxypicolinic
acid (3.9 g, 26 mmol) was added 40% aqueous H2SO4 (125 mL) at room
temperature. The
mixture was then warmed and stirred overnight at 90 C. After HPLC analysis
indicated the
reaction was complete, the reaction mixture was cooled to 5 C, and 25%
aqueous NaOH
(-250 mL) was charged slowly to the reaction mixture to adjust the pH to about
1-2. The
resulting suspension was stirred for 10-15 minutes at room temperature and the
solid product
was collected by filtration. The filter cake was washed with water and dried
in air for several
hours and then in a vacuum oven at 50 C to give 3-hydroxy-4-methoxypicolinic
acid (3.1 g)
as a brown solid in 70% yield: m.p. 227 C. 'FINMR (400 MHz, DMSO-d6) .3 8.04
(d, J =
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6.4 Hz, 1H), 7.40 (d, J= 6.5 Hz, 1H), 4.04 (s, 3H); "C NMR (101 MHz, DMSO-d6)
6
164.16, 162.03, 152.52, 132.32, 126.57, 109.13, 57.35.
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